Small-Molecule Modulation of the Circadian Clock in Cancer and Aging.

Circadian rhythms are ~24 h cycles regulated by an internal molecular clock. Disruption of this timing system has been implicated in numerous diseases, including the advancement of cancers and declines in function associated with aging. In recent years, scientists have identified various small molecules that can modulate core circadian clock proteins and pathways, providing potential therapeutic strategies to correct circadian dysfunction. This review presents a thorough overview of circadian clock mechanisms and highlights known small-molecule modulators. We describe how these compounds were discovered (through high-throughput screening and rational design) and categorize them based on their molecular targets. This review also summarizes key findings in cancer models, where clock-modulating compounds affect tumor metabolism, cell proliferation, and responsiveness to treatments, as well as in aging models, where strengthening circadian function may enhance metabolic health and longevity. Additionally, we cover clinical and preclinical studies involving these molecules and address challenges such as off-target effects and the complex nature of clock regulation. Finally, we outline future directions, emphasizing the development of new chronotherapeutics and the incorporation of circadian modulation into interventions for cancer and aging.